We have established a unique, population-based study of non-melanoma skin cancer (i.e., keratinocyte cancers) in New Hampshire that has made several important scientific and public health contributions. In the absence of central registries, we have provided incidence data to inform time trends of these malignancies. In the previous grant periods we identified a substantial increase in the incidence rates of the two major forms of keratinocyte cancers: basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) of the skin, with a dramatic rise in SCC, particularly among women. Moreover, we have identified many important non-solar risk factors that contribute to these highly prevalent cancers. Our population approach also has allowed us to detect novel molecular-genetic alterations in keratinocyte tumors, and to apply molecular epidemiologic methods to help establish causal relationships. In this continuation period, we will determine whether invasive SCC incidence rates continue to rise steeply, especially among women. We will evaluate incidence trends spanning a 30 year period (1979/801993- 2010), and for the first time examine birth cohort patterns. We propose to continue the case-control study to address emerging potentially carcinogenic exposures (e.g., tanning beds and booths, photosensitizing agents, oral contraceptives, hair dyes and tattoos) along with hypothesized chemopreventive agents such as tea and non-steroidal anti-inflammatory drugs. Additionally, we will investigate epidemiologic determinants of SCC classified according to hedgehog pathway alteration. To achieve these aims, we will continue our successful methods for subject identification, recruitment, interviewing, and tissue attainment. We will continue to identify newly diagnosed SCCs through our state- wide active surveillance network of dermatplogists, dermatopathologists and pathology laboratories. We will prospectively enlist 750 SCC cases ages 25 to 74 years and 750 age matched controls from population lists (Department of Transportation and Medicare enrollment files). We will conduct a standardized in-person interview, request a blood (or buccal) tissue sample and permission to obtain pathology materials. We then will perform fine deletion mapping of the PTCH gene in the original diagnostic tumor. Using our comprehensive approach we can identify avoidable risk factors for the most common forms of cancer in the US that can apply to other malignancies. Further, our findings will provide mechanistic insights into cancer pathogenesis and molecular targets for cancer prevention. Relevance: Squamous cell skin cancers, often invasive and disfiguring, are increasing at a steep rate making them one of the most common cancers in the US and of great public health concern. We will use epidemiologic tools to identify environmental risks and potential preventative measures that impact these cancers, to help inform both policymakers and health care providers in reducing the burden of these cancers on the US population.